Synthesis and antimicrobial evaluation of piperic acid amides and their lower homologues.

Seven piperic acid amides along with their lower homologs (12) were synthesized using HATU-DIPEA coupling reagent. All the synthesized derivatives were evaluated for their antibacterial activities against Staphylococcus aureus, Pseudomonas aeruginosa, and vancomycin-resistant P. aeruginosa. They were found to be more active on P. aeruginosa than on S. aureus. However, they did not exhibit potent activity on Vancomycin resistant P. aeruginosa. Among the tested compounds, methylenedioxycinnamic acid amide of anthranilic acid (MDCA-AA, 2a) was found to be most active against S. aureus with MIC of 3.125 µg/ml. The PAS and INH amides of piperic acid were screened against Mycobacterium tuberculosis H37Ra strain. They were found to be most active among all the tested compounds but were found to be less active than the standard drug, isoniazid.

Synthesis, Antimycobacterial Evaluation and Docking Studies of Some 7-Methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones.

Two series of 3-substituted-7-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5] thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7,2-dimethyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were synthesized and characterized using spectral data i.e., IR, 1H-, 13C-NMR, Mass and CHN elemental analyses. The synthesized compounds were evaluated for antibacterial activity against each of two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria and antimycobacterial activity screened against two strains i.e., Mycobacterium tuberculosis (MTB) H37Rv and an isoniazid-resistant clinical sample. Further to validate potentiality of our design was analyzed using molecular docking studies by taking crystal structure of MTB pantothenate synthetase (MTB-PS) (PDB: 3IVX). In this study, some compounds 6k (Minimum Inhibitory Concentration (MIC): MIC-22 µM), 7d (MTB: MIC-22 µM) and 7k (MTB: MIC-11 µM) showed potential antibacterial and antimycobacterial activities.

Focused screening to identify new adenosine kinase inhibitors.

Adenosine kinase (AdK) is a key player in controlling intra- and extracellular concentrations of the signaling molecule adenosine. Extensive evidence points to an important role of AdK in several diseases, and suggests that AdK inhibition might be a promising therapeutic strategy. The development of a new AdK assay and subsequent screening of part of our focused compound library led to the identification of 12 hit compounds (hit rate of 6%) representing six new classes of non-nucleoside human AdK inhibitors. The most potent inhibitor 1 displayed a Ki value of 184nM. Compound screening with a newly developed assay was useful and efficient for discovering novel AdK inhibitors which may serve as lead structures for developing drugs for adenosine augmentation therapy.

Molecular docking and receptor-specific 3D-QSAR studies of acetylcholinesterase inhibitors.

The reversible inhibition of acetylcholinesterase (AChE) has become a promising target for the treatment of Alzheimer's disease (AD) which is mainly associated with low in vivo levels of acetylcholine (ACh). The availability of AChE crystal structures with and without a ligand triggered the effort to find a structure-based design of acetylcholinesterase inhibitors (AChEIs) for AD. The major problem observed with the structure-based design was the feeble robustness of the scoring functions toward the correlation of docking scores with inhibitory potencies of known ligands. This prompted us to develop new prediction models using the stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LigandFit, and GLIDE). In the present investigation, a dataset of 91 molecules belonging to 9 different structural classes of heterocyclic compounds with an activity range of 0.008 to 281,000 nM was considered for docking studies and development of AChE-specific 3D-QSAR models. The model (M1) developed using consensus of docking scores of scoring functions viz. Glide score, Gold score, Chem score, ASP score, PMF score, and DOCK score was found to be the best (R(2) = 0.938, Q(2) = 0.925, R(pred)(2) = 0.919, R(2)m((overall)) = 0.936) compared to other consensus models. Docking studies revealed that the molecules with proper alignment in the active site gorge and the ability to interact with all the crucial amino acid residues, in particular by forming π-π stacking interactions with Trp84 at the catalytic anionic site (CAS) and Trp279 at peripheral anionic site (PAS), showed augmented potencies with consequent improvement in patient cognition and reduced the formation of senile plaques associated with AD. Further, the descriptors that signify the association of the ligands with the receptor as well as ADME properties of the ligands were also analyzed by means of the set of ligands that have been pre-positioned with respect to a receptor after docking analysis and considered as independent variables to generate a linear model (M3 and M4) using a stepwise multiple linear regression method to get additional insight into the physicochemical requirements for effective binding of ligands with AChE as well as for prediction of AChE inhibition. The developed AChE-specific prediction models (M1-M4) satisfactorily reflect the structure-activity relationship of the existing AChEIs and have all the potential to facilitate the process of design and development of new potent AChEIs.

An improved synthesis of lysosomal activated mustard prodrug for tumor-specific activation and its cytotoxic evaluation.

Cyclophosphamide, an alkylating agent widely used as anticancer agent, biotransformed in vivo to unstable phosphoramidic mustard and acrolein, where the latter metabolite has been found responsible for hemorrhagic cystitis and renal toxicity. Being one of the most popular strategies to avoid these deleterious effects, prodrug design has been attempted, which can, in addition, enable selective drug targeting. Our efforts to design, synthesize and evaluate the enzymatically activated prodrug phosphorodiamidic mustard as potential candidate for selective chemotherapy in antibody-directed enzyme prodrug therapy or prodrug monotherapy strategies are described. We propose an improved synthesis of prodrug 14, consisting of a galactose moiety, a spacer and a cytotoxic drug and its cytotoxicity has been investigated. The prodrug 14 has been found to be nontoxic (in vitro) which could be a valuable candidate for further development.

Evaluation of drug utilization in cardiovascular disease at a teaching and referral hospital in Northern Telangana.

OBJECTIVES: Cardiovascular disease (CVD) is the primary cause of death globally despite the advanced health-care facilities. Extensive disparity exists in pharmacotherapy pattern among CVD patients where rational drug use plays a pivotal role in promoting safety and efficacy. The study focused to evaluate drug utilization using the World Health Organization (WHO) prescribing indicators and defined daily dose (DDD) in patients admitted to a teaching/referral hospital in Northern Telangana. MATERIALS AND METHODS: A total of 1120 medical records were analyzed for drug utilization for a period of 7 months. Prescription pattern was assessed using the WHO prescribing indicators and DDD to measure individual drug utilization categorized under anatomical-therapeutic-chemical classification. RESULTS: Of the total admissions, 58.57% (55.19 ± 15.19 years) were male and 41.43% (56.64 ± 15.28 years) were female where coronary artery disease was the most common cause of admission followed by cardiomyopathy. Among prescribing indicators, percentage of drugs with generic names was least accounted with 26.86% and 18.95% during hospitalization and discharge, respectively. A mean of 11.55 (hospitalization) and 6.55 (discharge) drugs were prescribed per prescription. Antiplatelet (72.86%) and statin (80.62%) use was predominate during complete therapy. The DDD of furosemide (109.33) was found to be high, followed by atorvastatin (64.6), enalapril (58.44), aspirin (58.14) and clopidogrel (53.2). CONCLUSION: Polypharmacy and least use of generic name were observed in the study which may affect the rationality. The use of antiplatelets, statins, and angiotensin-converting enzyme-inhibitors was appropriate, but furosemide overuse is of major concern. Therefore, appropriate prescription writing improvises treatment compliance in the patients, which results in rationality.

Safety, pharmacokinetics and biodistribution studies of a beta-galactoside prodrug of doxorubicin for improvement of tumor selective chemotherapy.

Anthracycline antibiotics, particularly doxorubicin (DOX) and daunorubicin, have been used extensively in the treatment of human malignancies. However, cardiotoxicity and multidrug resistance are significant problems that limit the clinical efficacy of such agents. Rational design to avoid these side effects includes strategies such as drug targeting and prodrug synthesis. The DOX prodrug N-(beta-D-glucopyranosylbenzyloxycarbonyl)-doxorubicin (prodrug 1) was synthesized for specific activation by beta-galactosidase, which is expected to release in necrotic areas of tumor lesions. Described here is the safety, pharmacokinetics, and biodistribution studies of a beta-galactoside prodrug of DOX. In vivo safety evaluation was done in the Ehrlich Ascites Carcinoma (EAC) tumor model. The dose of DOX was 8 mg/kg and the dose of prodrug was 8 mg/kg and 24 mg/kg of DOX equivalents. Our results on cytotoxicity, which demonstrated compression in the number of EAC cells and their viability, substantiate these data. Prodrug 1 was safe up to a dose of 24 mg/kg of DOX equivalents in EAC mice. The pharmacokinetics and biodistribution of prodrug (300 mg/kg) in normal mice were determined and compared with DOX (20 mg/kg). Administration of DOX in normal mice resulted in a peak plasma concentration of 19.45 microM (t = 30 minutes). Prodrug injection resulted in 3- to 16-fold lower concentrations in the tissues of normal mice. As it is more polar, lower levels were observed in tissues and plasma in contrast to the parent compound DOX. In vivo safety studies have shown that prodrug 1 had a maximum tolerated dose compared with DOX and led to improved pharmacokinetics in normal mice.

Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3-d]pyrimidine derivatives.

A series of new molecules containing a thieno[2,3-d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2-position as well as an oxo-group, imidazole or 1,2,4-triazole ring at 4-position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17-19 with a free amino group at 2-position along with the presence of an imidazole/1,2,4-triazole ring at 4-position of the scaffold showed selective binding affinities for hA2A AR, whereas carbamoylation of the amino group at 2-position (in the presence of an oxo-group at 4-position of the scaffold) increased the affinity and selectivity of certain compounds (7-10) for hA3 AR. Molecular dynamic simulation study of one of the most active compound 8 (Ki hA1  > 30 µm, hA2A  = 0.65 µm, and hA3  = 0.124 µm) revealed the role of important amino acid residues for imparting good affinity towards hA3 and hA2A ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA2A AR and a homology model of hA3 AR to rationalize their structure-activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.

Beta-galactoside prodrugs of doxorubicin for application in antibody directed enzyme prodrug therapy/prodrug monotherapy.

Anthracycline antibiotics, particularly doxorubicin and daunorubicin, have been used exten sively in the treatment of human malignancies. However cardiotoxicity and multidrug resistance are significant problems that limit the clinical efficacy of such agents. Rational design to avoid these side effects includes strategies such as drug targeting and prodrug synthesis. Described here are the synthesis and preliminary biological evaluation of the enzymatically activated two new prodrugs (6 & 11) of doxorubicin. These prodrugs were designed as potential candidates for selective chemotherapy in ADEPT or PMT strategies. They are constituted of a galactose moiety, a spacer and the cytotoxic drug and they differ by the type of spacer. The prodrugs were stable in a buffer, and the in vitro studies showed good detoxification and hydrolysis kinetics. As prodrug 11 was readily hydrolyzed, this could be a valuable candidate for further development.

2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure-Activity Relationships of Potent Adenosine Receptor Antagonists.

2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A3 AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, Ki human A3 AR 1.16 nm) and 5'-phenyl-1,2-dihydro-3'H-spiro[indole-3,2'-[1,2,4]triazolo[1,5-c]quinazolin]-2-one (20, Ki human A3 AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A1 /A3 antagonist 2,5-diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13 b, Ki human A1 AR 51.6 nm, human A3 AR 11.1 nm), and the balanced pan-AR antagonists 5-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, Ki human A1 AR 131 nm, A2A AR 32.7 nm, A2B AR 150 nm, A3 AR 47.5 nm) and 9-bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 q, Ki human A1 AR 67.7 nm, A2A AR 13.6 nm, A2B AR 75.0 nm, A3 AR 703 nm). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.

New malabaricane triterpenes from the oleoresin of Ailanthus malabarica.

Ten malabaricane type triterpenes were isolated from the oleoresin of Ailanthus malabarica, out of which six (1-6) were new. For three of the known compounds (7-9), NMR assignments are being reported for the first time. Compound 10, a known one, is a new report from this source. The structures were established by extensive 1D and 2D NMR spectroscopy. The oleoresin and some of the isolates did not possess antimicrobial activity and did not lyse RBCs.

Pharmacophore based 3D-QSAR study of biphenyl derivatives as nonsteroidal aromatase inhibitors in JEG-3 cell lines.

Breast cancer is one of the most high-profile malignant diseases in modern society. Among postmenopausal women affected by the disease, a substantial portion has breast tumors that are estrogen-receptor positive. A common therapeutic intervention for this type of cancer is through endocrine therapy. Endocrine agents can act by either diminishing the availability or inhibiting the binding of estrogens to ER. Aromatase catalyzes the conversion of androgens to estrogens in the final step of the biosynthesis of estrogens and is therefore an attractive therapeutic target for inhibition. 3DQSAR pharmacophore modeling studies were undertaken for biphenyl derivatives as aromatase inhibitors in JEG-3 cell lines. A four-point pharmacophore with two H-bond acceptors and two aromatic rings as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R² = 0.977 for training set molecules. The generated model showed excellent predictive power, with a correlation coefficient of Q² = 0.946 for an external test set. The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may help in the design and development of potent biphenyl derivatives as new aromatase inhibitors.

Synthesis and antibacterial activity of a new series of 2,3,5,7-substituted-pyrido[2,3-d]pyrimidin-4(3h)-one derivatives.

A new series of 2,3,5,7-substituted-pyrido[2,3-d]pyrimidin-4(3H)-one derivatives were prepared from 2-amino-N,6-substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides. The key intermediate 2-amino-N,6-substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides were synthesized from 2-bromo-N,6-disubstituted phenyl-4-(trifluoromethyl or methyl)nicotinamides as well as from ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) coupling of 2-amino-4,6-substituted nicotinic acid and substituted arylamines. All the synthesized compounds were screened for antibacterial activity against Gram +ve and Gram -ve bacteria. Compound 7c showed better antibacterial activity against Gram +ve and Gram -ve bacteria.